Evaluation of the role of NMDA-mediated excitotoxicity in the selective neuronal loss in experimental Wernicke encephalopathy.
The goal of the studies described was to evaluate the role of NMDA receptor-mediated glutamate excitotoxicity in the pathogenesis of selective neuronal loss due to thiamine deficiency. Administration of the central thiamine antagonist pyrithiamine to adult male rats resulted in a sequence of neurological symptoms including ataxia and loss of righting reflex followed by convulsions. Prior to the onset of convulsions, neuropathologic evaluation revealed significant neuronal loss in the ventral posterior medial thalamic nucleus. However, in vivo cerebral microdialysis at preconvulsive stages did not demonstrate significant increases of extracellular glutamate in this region and pretreatment with the NMDA receptor antagonist MK801 (1 mg/ kg/12 h, i.p.) did not afford significant neuroprotection. Following the onset of convulsions, microdialysate glutamate concentrations were increased fivefold (P > 0.05) and MK801 treatment resulted in significant attenuation of neuronal loss in some thalamic nuclei. A comparable degree of neuroprotection was afforded by pretreatment with an anticonvulsant dose of diazepam (10 mg/kg/12 h, i.p.) a compound whose action is not NMDA receptor mediated. These findings suggest that NMDA receptor-mediated excitotoxicity is not responsible for early selective neuronal loss in this model of thiamine deficiency encephalopathy and that the neuroprotective effect of MK801 at later stages are at least in part a consequence of its anticonvulsant properties.
Todd
K G
KG
Neuroscience Research Unit, André-Viallet Clinical Research Center, Hôpital Saint-Luc (University of Montreal), Quebec, Canada.
Butterworth
R F
RF
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D001522:Behavior, Animal / Q000502:physiology; D002452:Cell Count; D016923:Cell Death / Q000502:physiology; D003975:Diazepam / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018698:Glutamic Acid / Q000502:physiology*; D008297:Male; D017551:Microdialysis; D009474:Neurons / Q000473:pathology / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D013832:Thiamine Deficiency / Q000473:pathology / Q000503:physiopathology; D014899:Wernicke Encephalopathy / Q000473:pathology / Q000503:physiopathology* / Q000523:psychology
D000927:Anticonvulsants; D018696:Neuroprotective Agents; D009498:Neurotoxins; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D003975:Diazepam